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Targeting effector pathways in RAC1(P29S)-driven malignant melanoma
Small GTPases. 2021 jul;12(4) :273-281
PMID: 32043900 PMCID: PMC8205048 URL: https://www.ncbi.nlm.nih.gov/pubmed/32043900
AbstractMalignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recent genomic analyses revealed that 4-9% of sun-exposed melanomas bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signalling from RAC1(P29S), we here extend this analysis to examine the roles of PI3Ks and SRF/MRTF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036), a pan-PI3K (BKM120), and two PI3Kbeta inhibitors (TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not by mutant BRAF, while other PI3K selective inhibitors, including PI3Kalpha, delta and gamma, are less effective. Using these compounds as well as an SRF/MRTF inhibitor (CCG-203,971), we observed similar results in vivo, using embryonic zebrafish development as a readout. These results suggest that targeting Group A PAKs, PI3Kbeta, and/or SRF/MRTF represent a promising approach to suppress RAC1 signalling in malignant melanoma.
Notes2154-1256 Uribe-Alvarez, Cristina Guerrero-Rodriguez, Sandra Lucia Rhodes, Jennifer ORCID: https://orcid.org/0000-0001-7298-1213 Cannon, Alexa Chernoff, Jonathan ORCID: https://orcid.org/0000-0002-4803-7836 Araiza-Olivera, Daniela Journal Article United States Small GTPases. 2020 Feb 17:1-9. doi: 10.1080/21541248.2020.1728469.